REST corepressor 2 also known as CoREST2 is a protein that in humans is encoded by the RCOR2 gene.
CoREST2 is a transcriptional corepressor protein that plays a pivotal role in regulating gene expression critical for stem cell pluripotency, neurogenesis, and cell fate determination. Predominantly expressed in embryonic stem cells and the central nervous system, RCOR2 partners with key complexes such as LSD1 to modulate chromatin structure and repress target genes, ensuring proper cell proliferation and differentiation.
A non-canonical role of RCoR2 (REST corepressor 2) has been described in adrenergic neuroblastoma, expanding its established function as a transcriptional corepressor. In this context, RCOR2, driven by a super-enhancer and functionally distinct from its paralogs, can act as a positive regulator that facilitates genomics contacts between core regulatory circuitry (CRC)-bound enhancers and their target core promoters, thereby sustaining gene-expression programs that preserve adrenergic cell identity and promote tumor cell proliferation. This activating behavior challenges the traditional view of RCOR2 as exclusively part of repressive complexes and highlights the functional plasticity of HDAC containing chromatin regulators in pediatric cancers, identifying RCOR2 as a potential therapeutic vulnerability in adrenergic neuroblastoma.